CN104262342A - Preparation method of istradefylline intermediate - Google Patents
Preparation method of istradefylline intermediate Download PDFInfo
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- CN104262342A CN104262342A CN201410436295.7A CN201410436295A CN104262342A CN 104262342 A CN104262342 A CN 104262342A CN 201410436295 A CN201410436295 A CN 201410436295A CN 104262342 A CN104262342 A CN 104262342A
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- diethyl
- dimethoxyphenyl
- purine
- dihydro
- vinyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
Abstract
The invention relates to a preparation method of an istradefylline intermediate, and provides a method for preparing a crude product of YQ-2 by using -1, 3-diethyl-6-amino-5- (3, 4-dimethoxyphenylpropenoyl) aminouracil (namely YQ-1) as a raw material and 1, 4-dioxane as a solvent, heating under the alkaline condition of NaOH aqueous solution, carrying out condensation and ring closure to generate -8- [2- (3, 4-dimethoxyphenyl) vinyl ] -1, 3-diethyl-3, 7-dihydro-1H-purine-2, 6-dione (namely YQ-2), and carrying out rotary evaporation, acid adjustment and suction filtration to obtain the crude product of YQ-2. And then using toluene as a solvent to recrystallize the crude YQ-2 product to obtain a refined YQ-2 product. The method has the advantages of simple route, easily obtained raw materials, mild conditions, convenient operation, total yield of more than 85 percent and purity of more than 97 percent, and is suitable for large-scale production.
Description
Technical field
The invention belongs to medical art, be specifically related to (E)-8-[2-(3,4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-diketone and preparation method thereof, this compounds can be used for the Parkinsonian medicine istradefylline of preparation treatment.
Background technology
Parkinson's disease are a kind of Progressive symmetric erythrokeratodermia incurable diseases.Although existing medicine can slow down the symptom of this disease and slow down the course of disease at present, still lack effective preventive medicine.Now to the treatment of this disease mainly based on Dopaminesubstitutive therapies, the most frequently used is dopaminergic thing, comprises levodopa and directly or indirectly dopamine-receptor stimulant.Although levodopa is the key agents for the treatment of Parkinson, due to its tolerance difference and untoward reaction is many, as vomiting, nonautonomy motion and dyskinesia, and its curative effect of life-time service reduces, therefore, in the urgent need to seeking a kind of new methods for the treatment of.And adenosine A
2Areceptor-blocking agent is considered to the one very potential therapy approach of tool, and istradefylline is a kind of selectivity A
2Areceptor-blocking agent, can be used as substituting or supplement therapy medicine of levodopa.
The chemical name of istradefylline is (E)-8-[2-(3, 4-Dimethoxyphenyl) vinyl]-1, 3-diethyl-3, 7-dihydro-7-methyl isophthalic acid H-purine-2, 6-diketone, Kyowa Hakko Kogyo Co., Ltd. of Japan discloses a kind of synthetic method of istradefylline in US Patent No. 005484920A, the method is with (E)-1, 3-diethyl-6 amino-5-(3, 4-dimethoxy phenylpropene acyl group) amino uracil (YQ-1) is raw material, through condensation ring-closure reaction under alkaline condition, chloroform extraction, silica gel chromatographic column method purifying, re crystallization from toluene obtains (E)-8-[2-(3, 4-Dimethoxyphenyl) vinyl]-1, 3-diethyl-3, 7-dihydro-1H-purine-2, 6-diketone (YQ-2), again with (E)-8-[2-(3, 4-Dimethoxyphenyl) vinyl]-1, 3-diethyl-3, 7-dihydro-1H-purine-2, 6-diketone (YQ-2) is raw material, methylate through methyl iodide, chloroform extraction, silica gel chromatographic column method purifying, recrystallisation from isopropanol obtains (E)-8-[2-(3, 4-Dimethoxyphenyl) vinyl]-1, 3-diethyl-3, 7-dihydro-7-methyl isophthalic acid H-purine-2, 6-diketone (YQCJ).The shortcoming of aforesaid method has used controlled drug trichloromethane, and the oxidizable product of trichloromethane has the phosgene of severe toxicity; Have employed silica gel chromatographic column method purified product in reaction in addition, route is loaded down with trivial details, consuming time, is unfavorable for amplifying producing.
Document " J Org Chem, 2004,69; 3308-3318 " provides two kinds of (E)-8-[2-(3,4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2, the preparation method of 6-diketone (YQ-2), the first take ethanol as solvent, and YQ-1 is through condensation closed loop in the basic conditions, then acid adjustment obtains YQ-2 crude product, but yield is lower, be only 62%; Second method is that YQ-1 and HMDS (hexamethyldisilane) and catalyst sulfuric acid ammonium obtain YQ-2 through 4 hours reaction condensation closed loops under 170-180 DEG C and condition of high voltage, yield is 92%, YQ-2 obtains (E)-8-[2-(3 again through methylating, 4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-7-methyl isophthalic acid H-purine-2,6-diketone (YQCJ).But this kind of method needs to use High Temperature High Pressure, be unfavorable for amplifying and produce.
Summary of the invention
The technical problem to be solved in the present invention for providing a kind of quality better, production technique simple istradefylline intermediate, and provides its preparation method, its processing method is easy, safe reliability good, purity and yield higher.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
With (E)-1, 3-diethyl-6 amino-5-(3, 4-dimethoxy phenylpropene acyl group) amino uracil (YQ-1) is starting raw material, under the NaOH aqueous solution alkaline condition of 1mol/L, 1, through condensation closed loop synthesis (E)-8-[2-(3 in 4 dioxane, 4-Dimethoxyphenyl) vinyl]-1, 3-diethyl-3, 7-dihydro-1H-purine-2, 6-diketone (YQ-2), afterwards reaction solution is revolved steaming to occurring a large amount of solid, under ice-water bath condition, slowly instillation concentrated hydrochloric acid regulates PH to be 2, suction filtration afterwards, filter cake is cleaned again with distilled water, filter cake is dried to constant weight, obtain YQ-2 crude product, again through re crystallization from toluene, obtain YQ-2 highly finished product.
The concrete preparation method of above-mentioned istradefylline intermediate comprises the steps:
(1) get (E)-1,3-diethyl-6 amino-5-(3,4-dimethoxy phenylpropene acyl group) amino uracil (YQ-1) be evenly dissolved in 1, in 4 dioxane, Isosorbide-5-Nitrae dioxane consumption is 5 ~ 20 times of YQ-1 quality, preferably 10 ~ 15 times amount;
(2) configure the NaOH aqueous solution of 1mol/L, consumption is 10 ~ 40 times of YQ-1 quality, preferably 20 ~ 30 times;
Insulation reaction 1 ~ 5h at (3) 110 ~ 130 DEG C, is cooled to less than 60 DEG C after reacting completely, afterwards reaction solution is carried out 60 ~ 90 DEG C of vacuum rotary steams to occurring a large amount of solid;
(4) under ice-water bath condition, slowly drip concentrated hydrochloric acid, regulate pH value to be 2;
(5) suction filtration, cleans filter cake with distilled water, and filter cake 50 DEG C is dried to constant weight, obtain (E)-8-[2-(3,4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-diketone crude product, i.e. YQ-2 crude product;
Above-mentioned reaction can specifically be expressed as follows:
(6) be dissolved in toluene by previous step gained YQ-2 crude product, toluene consumption is 5 ~ 20 times of YQ-2 crude product quality, preferably 8 ~ 15 times;
(7) (E)-8-[2-(3,4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2, the temperature of 6-diketone crude product re crystallization from toluene is 120 ~ 140 DEG C, and the time of recrystallization is 1 ~ 6 hour; Recrystallization temperature preferably 125 ~ 135 DEG C, time preferably 3 ~ 5h, the HPLC monitoring reaction of recrystallization, be cooled to room temperature after reacting completely, suction filtration, toluene cleaning filter cake, filter cake 50 DEG C is dried to constant weight, obtains YQ-2 highly finished product.
The present invention's one synthesis (E)-8-[2-(3,4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2, the method of 6-diketone, cancel and use tubing products trichloromethane and high temperature and pressure experiment condition, test operation security is greatly carried and being added; Cancel and use silica gel chromatographic column method purified product, test simplicity improves greatly; Steaming is revolved in employing, the post-treating method istradefylline intermediate purification product purity that recrystallization obtains again of acid adjustment reaches more than 97%, and total recovery is more than 85%, and intermediate quality is high, and technological operation is convenient, and raw material economics, is applicable to large-scale industrial production.
accompanying drawing explanation
Fig. 1 is embodiment 1 finished product liquid chromatogram
Fig. 2 is embodiment 2 finished product liquid chromatogram
Fig. 3 is embodiment 3 finished product liquid chromatogram
Fig. 4 is embodiment 4 finished product liquid chromatogram
embodiment
Embodiment 1
Get the there-necked flask of clean 5000ml, pour the Isosorbide-5-Nitrae dioxane of 485ml into; pour the NaOH aqueous solution of 960ml1mol/L again into; add (E)-1,3-diethyl-6 amino-5-(3,4-dimethoxy phenylpropene acyl group) the amino uracil 100g (0.258mol) accurately taken again; oil bath is heated; be warming up to 110 DEG C, to occurring backflow, mechanical stirring 1 hour; there-necked flask lucifuge in reaction process, HPLC monitors extent of reaction.After reaction terminates, be cooled to about 60 DEG C, reaction solution be transferred to 60 DEG C of vacuum rotary steams in 5L single port bottle, to bottle, occur that a large amount of yellow solid stops revolving steaming.Be transferred to by the mashed prod revolving steaming end in the 5L single port bottle of lowering the temperature with ice bag and frozen water, slowly dropping concentrated hydrochloric acid is adjusted to pH value is 2.To the mashed prod suction filtration of acid be adjusted, and add about 100ml and distill moisture 2 cleaning filter cakes.Afterwards the filter cake 50 DEG C after cleaning is dried to constant weight, obtain (E)-8-[2-(3,4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-diketone crude product 87.7g, yield 91.97%.
Get the there-necked flask of clean 2000ml, add compound (E)-8-[2-(3 obtained, 4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-diketone crude product 87.7g (0.242mol), add the toluene of 520ml, oil bath is heated to 120 DEG C, mechanical stirring 1 hour, there-necked flask lucifuge in reaction process.Suction filtration after cooling, with 90ml toluene cleaning filter cake, dry the filter cake 50 DEG C after cleaning to constant weight afterwards, obtain yellow solid highly finished product 82.2g, yield 93.72%, content 97.27%, is shown in Fig. 1.
Embodiment 2
Get the there-necked flask of clean 5000ml, pour the Isosorbide-5-Nitrae dioxane of 970ml into; pour the NaOH aqueous solution of 1920ml1mol/L again into; add (E)-1,3-diethyl-6 amino-5-(3,4-dimethoxy phenylpropene acyl group) the amino uracil 100g (0.258mol) accurately taken again; oil bath is heated; be warming up to 115 DEG C, to occurring backflow, mechanical stirring 2 hours; there-necked flask lucifuge in reaction process, HPLC monitors extent of reaction.After reaction terminates, be cooled to about 60 DEG C, reaction solution be transferred to 70 DEG C of vacuum rotary steams in 5L single port bottle, to bottle, occur that a large amount of yellow solid stops revolving steaming.Be transferred to by the mashed prod revolving steaming end in the 5L single port bottle of lowering the temperature with ice bag and frozen water, slowly dropping concentrated hydrochloric acid is adjusted to pH value is 2.To the mashed prod suction filtration of acid be adjusted, and add about 100ml and distill moisture 2 cleaning filter cakes.Afterwards the filter cake 50 DEG C after cleaning is dried to constant weight, obtain (E)-8-[2-(3,4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-diketone crude product 88.6g, yield 92.91%.
Get the there-necked flask of clean 2000ml, add compound (E)-8-[2-(3 obtained, 4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-diketone crude product 88.6g (0.239mol), add the toluene of 820ml, oil bath is heated to 125 DEG C, mechanical stirring 3 hours, there-necked flask lucifuge in reaction process.Suction filtration after cooling, with 90ml toluene cleaning filter cake, dry the filter cake 50 DEG C after cleaning to constant weight afterwards, obtain yellow solid highly finished product 84.7g, yield 95.60%, content 98.54%, is shown in Fig. 2.
Embodiment 3
Get the there-necked flask of clean 10000ml, pour the Isosorbide-5-Nitrae dioxane of 1450ml into; pour the NaOH aqueous solution of 2880ml1mol/L again into; add (E)-1,3-diethyl-6 amino-5-(3,4-dimethoxy phenylpropene acyl group) the amino uracil 100g (0.258mol) accurately taken again; oil bath is heated; be warming up to 125 DEG C, to occurring backflow, mechanical stirring 4 hours; there-necked flask lucifuge in reaction process, HPLC monitors extent of reaction.After reaction terminates, be cooled to about 60 DEG C, reaction solution be transferred to 80 DEG C of vacuum rotary steams in 5L single port bottle, to bottle, occur that a large amount of yellow solid stops revolving steaming.Be transferred to by the mashed prod revolving steaming end in the 5L single port bottle of lowering the temperature with ice bag and frozen water, slowly dropping concentrated hydrochloric acid is adjusted to pH value is 2.To the mashed prod suction filtration of acid be adjusted, and add about 100ml and distill moisture 2 cleaning filter cakes.Afterwards the filter cake 50 DEG C after cleaning is dried to constant weight, obtain (E)-8-[2-(3,4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-diketone crude product 88.0g, yield 92.28%.
Get the there-necked flask of clean 5000ml, add compound (E)-8-[2-(3 obtained, 4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-diketone crude product 88g (0.238mol), add the toluene of 1520ml, oil bath is heated to 135 DEG C, mechanical stirring 5 hours, there-necked flask lucifuge in reaction process.Suction filtration after cooling, with 90ml toluene cleaning filter cake, dry the filter cake 50 DEG C after cleaning to constant weight afterwards, obtain yellow solid highly finished product 85.3g, yield 96.93%, content 98.76%, is shown in Fig. 3.
Embodiment 4
Get the there-necked flask of clean 10000ml, pour the Isosorbide-5-Nitrae dioxane of 1940ml into; pour the NaOH aqueous solution of 3840ml1mol/L again into; add (E)-1,3-diethyl-6 amino-5-(3,4-dimethoxy phenylpropene acyl group) the amino uracil 100g (0.258mol) accurately taken again; oil bath is heated; be warming up to 130 DEG C, to occurring backflow, mechanical stirring 5 hours; there-necked flask lucifuge in reaction process, HPLC monitors extent of reaction.After reaction terminates, be cooled to about 60 DEG C, reaction solution be transferred to 90 DEG C of vacuum rotary steams in 5L single port bottle, to bottle, occur that a large amount of yellow solid stops revolving steaming.Be transferred to by the mashed prod revolving steaming end in the 5L single port bottle of lowering the temperature with ice bag and frozen water, slowly dropping concentrated hydrochloric acid is adjusted to pH value is 2.To the mashed prod suction filtration of acid be adjusted, and add about 100ml and distill moisture 2 cleaning filter cakes.Afterwards the filter cake 50 DEG C after cleaning is dried to constant weight, obtain (E)-8-[2-(3,4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-diketone crude product 85.3g, yield 89.45%.
Get the there-necked flask of clean 5000ml, add compound (E)-8-[2-(3 obtained, 4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-diketone crude product 85.3g (0.231mol), add the toluene of 1970ml, oil bath is heated to 140 DEG C, mechanical stirring 6 hours, there-necked flask lucifuge in reaction process.Suction filtration after cooling, with 90ml toluene cleaning filter cake, dry the filter cake 50 DEG C after cleaning to constant weight afterwards, obtain yellow solid highly finished product 81.1g, yield 95.07%, content 98.17%, is shown in Fig. 4.
Obviously, above-described embodiment is only for clearly example being described, and the restriction not to embodiment.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here exhaustive without the need to also giving all embodiments.And thus the apparent change of amplifying out or variation be still in the protection domain of the invention.
Claims (7)
1. the preparation method of an istradefylline intermediate, it is characterized in that: with (E)-1, 3-diethyl-6 amino-5-(3, 4-dimethoxy phenylpropene acyl group) amino uracil is starting raw material, under the NaOH aqueous solution alkaline condition of 1mol/L, with 1, 4 dioxane are solvent, (E)-8-[2-(3 is generated through condensation ring-closure reaction, 4-Dimethoxyphenyl) vinyl]-1, 3-diethyl-3, 7-dihydro-1H-purine-2, 6-diketone, afterwards by reaction solution vacuum rotary steam to occurring a large amount of solid, under ice-water bath condition, slowly instillation concentrated hydrochloric acid regulates pH value to be 2, suction filtration afterwards, filter cake is cleaned with distilled water, filter cake 50 DEG C is dried to constant weight, obtain (E)-8-[2-(3, 4-Dimethoxyphenyl) vinyl]-1, 3-diethyl-3, 7-dihydro-1H-purine-2, 6-diketone crude product, use re crystallization from toluene again, room temperature is cooled to after recrystallization is complete, suction filtration, filter cake is cleaned with toluene, filter cake 50 DEG C is dried to constant weight, obtain (E)-8-[2-(3, 4-Dimethoxyphenyl) vinyl]-1, 3-diethyl-3, 7-dihydro-1H-purine-2, 6-diketone highly finished product, the mass ratio of the described NaOH aqueous solution and starting raw material is 10 ~ 40: 1, described 1, the mass ratio of 4 dioxane and starting raw material is 5 ~ 20: 1, described toluene and (E)-8-[2-(3, 4-Dimethoxyphenyl) vinyl]-1, 3-diethyl-3, 7-dihydro-1H-purine-2, the mass ratio of 6-diketone crude product is 5 ~ 20: 1.
2. the preparation method of istradefylline intermediate as claimed in claim 1, it is characterized in that: the described condensation ring-closure reaction time is 1 ~ 5 hour, described condensation ring-closure reaction temperature is 110 ~ 130 DEG C.
3. the preparation method of istradefylline intermediate as claimed in claim 1 or 2, it is characterized in that: the mass ratio of the described NaOH aqueous solution and starting raw material is 20 ~ 30: 1, the mass ratio of described Isosorbide-5-Nitrae dioxane and starting raw material is 10 ~ 15: 1.
4. the preparation method of istradefylline intermediate as claimed in claim 1, is characterized in that: after condensation ring-closure reaction terminates, and by reaction solution vacuum rotary steam, revolving and steaming temperature is 60 ~ 90 DEG C.
5. the preparation method of istradefylline intermediate as claimed in claim 1, it is characterized in that: (E)-8-[2-(3,4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3,7-dihydro-1H-purine-2, the temperature of 6-diketone crude product recrystallization is 120 ~ 140 DEG C, (E)-8-[2-(3,4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3, the time of 7-dihydro-1H-purine-2,6-diketone crude product recrystallization is 1 ~ 6 hour.
6. the preparation method of the istradefylline intermediate as described in claim 1 or 5, it is characterized in that: toluene and (E)-8-[2-(3,4-Dimethoxyphenyl) vinyl]-1,3-diethyl-3, the mass ratio of 7-dihydro-1H-purine-2,6-diketone crude product is 8 ~ 15: 1.
7. the preparation method of istradefylline intermediate as claimed in claim 6, it is characterized in that: described recrystallization temperature of reaction is 125 ~ 135 DEG C, the time of described recrystallization is 3 ~ 5 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864096A (en) * | 2017-05-08 | 2018-11-23 | 江苏恒瑞医药股份有限公司 | A kind of istradefylline bulk pharmaceutical chemicals and preparation method thereof |
| CN110041330A (en) * | 2018-01-16 | 2019-07-23 | 新发药业有限公司 | A kind of environment-friendly preparation method of istradefylline |
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| US5543415A (en) * | 1992-07-08 | 1996-08-06 | Kyowa Hakko Kogyo Co., Ltd. | Antidepressants |
| US5587378A (en) * | 1992-04-08 | 1996-12-24 | Kyowa Hakko Kogyo Co., Ltd. | Therapeutic agent for Parkinson's disease |
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| US5587378A (en) * | 1992-04-08 | 1996-12-24 | Kyowa Hakko Kogyo Co., Ltd. | Therapeutic agent for Parkinson's disease |
| US5543415A (en) * | 1992-07-08 | 1996-08-06 | Kyowa Hakko Kogyo Co., Ltd. | Antidepressants |
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| JORG HOCKEMEYER等: "Multigram-Scale Syntheses, Stability, and Photoreactions of A2A Adenosine Receptor Antagonists with 8-Styrylxanthine Structure: Potential Drugs for Parkinson"s Disease", 《J. ORG. CHEM.》 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864096A (en) * | 2017-05-08 | 2018-11-23 | 江苏恒瑞医药股份有限公司 | A kind of istradefylline bulk pharmaceutical chemicals and preparation method thereof |
| CN108864096B (en) * | 2017-05-08 | 2020-05-05 | 江苏恒瑞医药股份有限公司 | Istradefylline bulk drug and preparation method thereof |
| CN110041330A (en) * | 2018-01-16 | 2019-07-23 | 新发药业有限公司 | A kind of environment-friendly preparation method of istradefylline |
| CN110041330B (en) * | 2018-01-16 | 2020-08-11 | 新发药业有限公司 | Environment-friendly preparation method of istradefylline |
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Address after: 210033 room 317, building F6, No.9, Weidi Road, Xianlin street, Qixia District, Nanjing City, Jiangsu Province Patentee after: Nanjing H&D Pharmaceutical Technology Co.,Ltd. Address before: 210033 room 317, building F6, No.9, Weidi Road, Xianlin street, Qixia District, Nanjing City, Jiangsu Province Patentee before: Nanjing H&D Pharmaceutical Technology Co.,Ltd. |
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| CP02 | Change in the address of a patent holder |
Address after: Building D3, No. 9, Weidi Road, Xianlin Street, Qixia District, Nanjing, Jiangsu 210033 Patentee after: Nanjing H&D Pharmaceutical Technology Co.,Ltd. Address before: 210033 room 317, building F6, No.9, Weidi Road, Xianlin street, Qixia District, Nanjing City, Jiangsu Province Patentee before: Nanjing H&D Pharmaceutical Technology Co.,Ltd. |